Objectives: Burnout syndrome is recognized as a major global problem among emergency healthcare workers as it causes prevalent fatigue, job separations, and disappointment. The objective of this study was to investigate the relationship of the glial marker S100B in sera of emergency physicians with burnout syndrome and depression.Methods: This was a prospective observational study of emergency medicine residents in three distinct university-based departments of emergency medicine. S100B levels were measured before and after the shifts. In addition, the resident completed the Maslach Burnout Inventory (MBI) and the Beck Depression Inventory (BDI) prior to starting the shift. S100B levels were compared to the occurrence of burnout syndrome and depression as measured by the MBI and BDI.Results: Forty-eight of 53 emergency medicine residents actively working in the three university-based EDs participated in the study. The majority of the sample had BDI scores compatible with severe depression (n = 37, 77.1%). The median scores of MBI for emotional exhaustion, depersonalization, and personal accomplishment were 29 (interquartile range [IQR] = 25 to 33), 14 (IQR = 12 to 18), and 26.5 (IQR = 22 to 31), respectively. S100B levels were found to correlate best with scores of BDI and emotional exhaustion in burnout syndrome. The difference between median S100B levels recorded in the residents with severe depression and moderate depression was found statistically significant ( Conclusions: S100B levels correlate with depression scores and emotional exhaustion in burnout syndrome. The findings suggest that S100B can be used as a marker to screen emergency medicine residents and detect individuals with high risk for depression and burnout syndrome.ACADEMIC EMERGENCY MEDICINE 2016;23:786-789